3, 4-Dihydroxyphenylacetic Acid (DOPAC) Impairs α-Synuclein Interaction with Lipids

α-Synuclein (α-Syn) is a small intrinsically disordered presynaptic protein known to form insoluble filamen- tous inclusions in Parkinson's disease (PD) and other neurodegenerative disorders. Various catecholamines can inhibit the α-Syn fibrillation in vitro. Recently, non-covalent binding of DOPAC (3,4-dihydroxyphenylacetic acid), a normal product of the dopamine metabolism, was shown to inhibit the fibrillation of α-Syn due to the DOPAC-induced stabilization of the normally transient oligomers thus preventing them from subsequent fibril formation (Zhou, et al. J. Mol. Biol. 2009, 388 (3), 597-610). We are showing here that the interaction of DOPAC with α-Syn decreases the binding affinity of α- Syn to lipids, suggesting that DOPAC might lead to the gain-of-toxicity of α-Syn aggregates and loss-of-function of α- Syn, both of which could be related to progression of PD.